Hepatitis C is a largely asymptomatic liver disease caused by the hepatitis C virus (HCV). HCV is an escalating public health problem and burdens an estimated 3% of the world's population. According to the World Health Organization (WHO), approximately 130-150 million individuals worldwide have been infected with HCV, and about 5,00,000 deaths occur due to HCV-related liver diseases each year. The viral disease is transmitted sexually or parenterally by contaminated blood, blood products, and needles or from infected mothers or carrier mothers to their offspring. HCV infected patients, due to the high percentage of individuals inflicted with chronic infections are at an elevated risk of developing cirrhosis of the liver, subsequent hepatocellular carcinoma and terminal liver disease. HCV is the most prevalent cause of hepatocellular cancer and of patients requiring liver transplantations in the western world.
HCV has an RNA genome, as it is an envelope, positive-sense, single-stranded virus. At least six genetic strains of HCV have been identified and studied. Based on a comparison of the deduced amino acid sequence and the extensive similarity in the 5′-untranslated region, HCV has been classified as a separate genus in the Flaviviridae family. All members of the Flaviviridae family have enveloped virions that contain a positive stranded RNA genome encoding all known virus-specific proteins via translation of a single, uninterrupted, open reading frame.
The single strand HCV RNA genome is approximately 9,500 nucleotides in length and has a single open reading frame (ORF) encoding a single large polyprotein of about 3,000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non-structural (NS) proteins. In the case of HCV, the generation of mature non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases. The first one is believed to be a metalloprotease and cleaves at the NS2-NS3 junction; the second one is a serine protease contained within the N-terminal region of NS3 (also referred to as NS3 protease) and mediates all the subsequent cleavages downstream of NS3, both in cis, at the NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NS5B sites. The NS4A protein appears to serve multiple functions, acting as a cofactor for the NS3 protease and possibly assisting in the membrane localization of NS3 and other viral replicase components. The complex formation of the NS3 protein with NS4A seems necessary to the processing events, enhancing the proteolytic efficiency at all of the sites. The NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities. NS5B (also referred to as HCV polymerase) is a RNA-dependent RNA polymerase that is involved in the replication of HCV.
A number of potential molecular targets for drug development of direct-acting antivirals (DAAs) as anti-HCV therapeutics have now been identified including, but not limited to, the NS2-NS3 autoprotease, NS4A protease, the N3 protease, the N3 helicase, and the NS5B polymerase.
HCV infection is currently treated with antiviral medications, e.g. pegylated interferon (Peg-IFN) administered alone or in combination with ribavirin. Combination therapy with pegylated interferon (Peg-IFN) and ribavirin (RBV) is now successful in about half of the cases, but it is currently prohibitively expensive, requires long-term treatment, and is associated with suboptimal efficacy, poorer efficacy among patients with certain genotypes and common severe side-effects that make the treatment intolerable for many patients. In much of the world, such treatments are not economically feasible. New direct-acting antiviral drugs such as protease and polymerase inhibitors, either with or without interferon and/or ribavirin, have the potential to increase the response rate and to decrease the duration of treatment. Challenges facing current treatment of HCV include lack of efficacy in patients with difficult-to-treat disease, such as patients with cirrhosis or infected with HCV genotype 1 (who represent a majority of US HCV infections), the toxicity of combination therapy, and the difficulty of therapy, and the poor reception of these treatments by many patients.
Although attempts have been made in the prior art to develop new treatment options, new therapies for treating HCV-infected patients are desired which selectively inhibit HCV viral replication. It takes a great deal of time and money to develop a new drug from a novel chemical compound, hence, it may be easier to use previously developed drugs that can be used for new applications. Giving due consideration to the diversity of the drugs that are in existence, a way forward could be to determine the activity of the existing drugs to address the need for an alternative treatment for hepatitis C.
Histone deacetylases are a class of enzymes that remove acetyl groups from lysine residues in histone proteins. A variety of compounds are known to inhibit this process, and these compounds are collectively referred to as histone deacetylase (HDAC) inhibitors. These compounds were historically used as mood stabilizers and anti-epileptics, and more recently have been explored for other pathophysiologies including neurodegenerative diseases, cancer and herpes virus.